Dynamics of the Peccei Quinn Scale

Invoking the Peccei-Quinn (PQ) solution to the strong CP problem substitutes the puzzle of why $\theta_{qcd}$ is so small with the puzzle of why the PQ symmetry is of such high quality. Cosmological and astrophysical considerations raise further puzzles. This paper explores this issues in several contexts: string theory and field theory, and theories without and with low energy supersymmetry. Among the questions studied are whether requiring axion dark matter can account for the quality of the PQ symmetry, to which the answer is sometimes yes. In non-supersymmetric theories, we find $f_a = 10^{12}$ GeV is quite plausible. In gauge mediation, cosmological constraints on pseudomoduli place $f_a$ in this range, and require that the gravitino mass be of order an MeV.Comment: 17 pages, 1 figur

The arrow of time, black holes, and quantum mixing of large N Yang-Mills theories

Quantum gravity in an AdS spacetime is described by an SU(N) Yang-Mills theory on a sphere, a bounded many-body system. We argue that in the high temperature phase the theory is intrinsically non-perturbative in the large N limit. At any nonzero value of the 't Hooft coupling $\lambda$, an exponentially large (in N^2) number of free theory states of wide energy range (of order N) mix under the interaction. As a result the planar perturbation theory breaks down. We argue that an arrow of time emerges and the dual string configuration should be interpreted as a stringy black hole.Comment: 50 pages 3 figures uses harvma

Human cachexia induces changes in mitochondria, autophagy and apoptosis in the skeletal muscle

Cachexia is a wasting syndrome characterized by the continuous loss of skeletal muscle mass due to imbalance between protein synthesis and degradation, which is related with poor prognosis and compromised quality of life. Dysfunctional mitochondria are associated with lower muscle strength and muscle atrophy in cancer patients, yet poorly described in human cachexia. We herein investigated mitochondrial morphology, autophagy and apoptosis in the skeletal muscle of patients with gastrointestinal cancer-associated cachexia (CC), as compared with a weight-stable cancer group (WSC). CC showed prominent weight loss and increased circulating levels of serum C-reactive protein, lower body mass index and decreased circulating hemoglobin, when compared to WSC. Electron microscopy analysis revealed an increase in intermyofibrillar mitochondrial area in CC, as compared to WSC. Relative gene expression of Fission 1, a protein related to mitochondrial fission, was increased in CC, as compared to WSC. LC3 II, autophagy-related (ATG) 5 and 7 essential proteins for autophagosome formation, presented higher content in the cachectic group. Protein levels of phosphorylated p53 (Ser46), activated caspase 8 (Asp384) and 9 (Asp315) were also increased in the skeletal muscle of CC. Overall, our results demonstrate that human cancer-associated cachexia leads to exacerbated muscle-stress response that may culminate in muscle loss, which is in part due to disruption of mitochondrial morphology, dysfunctional autophagy and increased apoptosis. To the best of our knowledge, this is the first report showing quantitative morphological alterations in skeletal muscle mitochondria in cachectic patients

Extracting the bulk metric from boundary information in asymptotically AdS spacetimes

We use geodesic probes to recover the entire bulk metric in certain asymptotically AdS spacetimes. Given a spectrum of null geodesic endpoints on the boundary, we describe two remarkably simple methods for recovering the bulk information. After examining the issues which affect their application in practice, we highlight a significant advantage one has over the other from a computational point of view, and give some illustrative examples. We go on to consider spacetimes where the methods cannot be used to recover the complete bulk metric, and demonstrate how much information can be recovered in these cases.Comment: 33 pages, 11 figures; v2 references adde

Myeloid-Specific Rictor Deletion Induces M1 Macrophage Polarization and Potentiates In Vivo Pro-Inflammatory Response to Lipopolysaccharide

The phosphoinositide-3-kinase (PI3K)/protein kinase B (Akt) axis plays a central role in attenuating inflammation upon macrophage stimulation with toll-like receptor (TLR) ligands. The mechanistic target of rapamycin complex 2 (mTORC2) relays signal from PI3K to Akt but its role in modulating inflammation in vivo has never been investigated. To evaluate the role of mTORC2 in the regulation of inflammation in vivo, we have generated a mouse model lacking Rictor, an essential mTORC2 component, in myeloid cells. Primary macrophages isolated from myeloid-specific Rictor null mice exhibited an exaggerated response to TLRs ligands, and expressed high levels of M1 genes and lower levels of M2 markers. To determine whether the loss of Rictor similarly affected inflammation in vivo, mice were either fed a high fat diet, a situation promoting chronic but low-grade inflammation, or were injected with lipopolysaccharide (LPS), which mimics an acute, severe septic inflammatory condition. Although high fat feeding contributed to promote obesity, inflammation, macrophage infiltration in adipose tissue and systemic insulin resistance, we did not observe a significant impact of Rictor loss on these parameters. However, mice lacking Rictor exhibited a higher sensitivity to sceptic shock when injected with LPS. Altogether, these results indicate that mTORC2 is a key negative regulator of macrophages TLR signalling and that its role in modulating inflammation is particularly important in the context of severe inflammatory challenges. These observations suggest that approaches aimed at modulating mTORC2 activity may represent a possible therapeutic approach for diseases linked to excessive inflammation.Howard Hughes Medical Institute (Investigator)National Institutes of Health (U.S.) (NIH grant CA103866)National Institutes of Health (U.S.) (NIH grant CA129105)National Institutes of Health (U.S.) (NIH grant AI47389)Canadian Institutes of Health ResearchNatural Sciences and Engineering Research Council of CanadaFonds de la recherche en santé du Québe

Hypoxia sustains glioblastoma radioresistance through ERKs/DNA-PKcs/HIF-1α functional interplay

The molecular mechanisms by which glioblastoma multiforme (GBM) refracts and becomes resistant to radiotherapy treatment remains largely unknown. This radioresistance is partly due to the presence of hypoxic regions, which are frequently found in GBM tumors. We investigated the radiosensitizing effects of MEK/ERK inhibition on GBM cell lines under hypoxic conditions. Four human GBM cell lines, T98G, U87MG, U138MG and U251MG were treated with the MEK/ERK inhibitor U0126, the HIF-1α inhibitor FM19G11 or γ-irradiation either alone or in combination under hypoxic conditions. Immunoblot analysis of specific proteins was performed in order to define their anti‑oncogenic or radiosensitizing roles in the different experimental conditions. MEK/ERK inhibition by U0126 reverted the transformed phenotype and significantly enhanced the radiosensitivity of T98G, U87MG, U138MG cells but not of the U251MG cell line under hypoxic conditions. U0126 and ERK silencing by siRNA reduced the levels of DNA protein kinase catalytic subunit (DNA-PKcs), Ku70 and K80 proteins and clearly reduced HIF-1α activity and protein expression. Furthermore, DNA-PKcs siRNA-mediated silencing counteracted HIF-1α activity and downregulated protein expression suggesting that ERKs, DNA-PKcs and HIF-1α cooperate in radioprotection of GBM cells. Of note, HIF-1α inhibition under hypoxic conditions drastically radiosensitized all cell lines used. MEK/ERK signal transduction pathway, through the sustained expression of DNA-PKcs, positively regulates HIF-1α protein expression and activity, preserving GBM radioresistance in hypoxic condition

Symmetric Points in the Landscape as Cosmological Attractors

In the landscape, if there is to be any prospect of scientific prediction, it is crucial that there be states which are distinguished in some way. The obvious candidates are states which exhibit symmetries. Here we focus on states which exhibit discrete symmetries. Such states are rare, but one can speculate that they are cosmological attractors. We investigate the problem in model landscapes and cosmologies which capture some of the features of candidate flux landscapes. In non-supersymmetric theories we find no evidence that such states might be cosmologically favored. In supersymmetric theories, simple arguments suggest that states which exhibit $R$ symmetries might be. Our considerations lead us to raise questions about some popular models of eternal inflation.Comment: 27 pages, latex, minor typo correcte

On a modular property of N=2 superconformal theories in four dimensions

In this note we discuss several properties of the Schur index of N=2 superconformal theories in four dimensions. In particular, we study modular properties of this index under SL(2,Z) transformations of its parameters.Comment: 23 page, 2 figure